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Nature communications
May 13, 2025;16 (1): 4269.

Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial.

Jean E Abraham, Lenka Oplustil O'Connor, Louise Grybowicz, Karen Pinilla Alba, Alimu Dayimu, Nikolaos Demiris, Caron Harvey, Lynsey M Drewett, Rebecca Lucey, Alexander Fulton, Anne N Roberts, Joanna R Worley, Ms Anita Chhabra, Wendi Qian, Jessica Brown, Richard Hardy, Anne-Laure Vallier, Steve Chan, Maria Esther Una Cidon, Elizabeth Sherwin, Amitabha Chakrabarti, Claire Sadler, Jen Barnes, Mojca Persic, Sarah Smith, Sanjay Raj, Annabel Borley, Jeremy P Braybrooke, Emma Staples, Lucy C Scott, Cheryl A Palmer, Margaret Moody, Mark J Churn, Domenic Pilger, Guido Zagnoli-Vieira, Paul W G Wijnhoven, Mukesh B Mukesh, Rebecca R Roylance, Philip C Schouten, Nicola C Levitt, Karen McAdam, Anne C Armstrong, Ellen R Copson, Emma McMurtry, Susan Galbraith, Marc Tischkowitz, Elena Provenzano, Mark J O'Connor, Helena M Earl, PARTNER Trial Group
Author Information
  1. Jean E Abraham: Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom. ja344@cam.ac.uk. ORCID
  2. Lenka Oplustil O'Connor: AstraZeneca, Cambridge, United Kingdom. ORCID
  3. Louise Grybowicz: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  4. Karen Pinilla Alba: Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom. ORCID
  5. Alimu Dayimu: Cambridge Clinical Trials Centre, Cancer Theme, University of Cambridge, Cambridge, United Kingdom.
  6. Nikolaos Demiris: Department of Statistics, Athens University of Economics and Business, Athens, Greece.
  7. Caron Harvey: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  8. Lynsey M Drewett: Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom.
  9. Rebecca Lucey: Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom. ORCID
  10. Alexander Fulton: Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
  11. Anne N Roberts: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  12. Joanna R Worley: Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
  13. Ms Anita Chhabra: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. ORCID
  14. Wendi Qian: Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. ORCID
  15. Jessica Brown: AstraZeneca, Cambridge, United Kingdom.
  16. Richard Hardy: Cambridge Clinical Trials Centre, Cancer Theme, University of Cambridge, Cambridge, United Kingdom.
  17. Anne-Laure Vallier: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  18. Steve Chan: The City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
  19. Maria Esther Una Cidon: Royal Bournemouth General Hospital, University Hospitals Dorset NHS Foundation Trust, Bournemouth, United Kingdom.
  20. Elizabeth Sherwin: Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich, United Kingdom.
  21. Amitabha Chakrabarti: University Hospitals Dorset NHS Foundation Trust, Poole, United Kingdom.
  22. Claire Sadler: Apconix Ltd, Alderley Edge, Cheshire, United Kingdom.
  23. Jen Barnes: AstraZeneca, Cambridge, United Kingdom.
  24. Mojca Persic: University Hospital of Derby and Burton, Derby, United Kingdom.
  25. Sarah Smith: Bedford Hospital, Bedfordshire Hospitals NHS Foundation Trust, Bedford, United Kingdom.
  26. Sanjay Raj: University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
  27. Annabel Borley: Velindre Cancer Centre, Cardiff, United Kingdom.
  28. Jeremy P Braybrooke: University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom.
  29. Emma Staples: Queens Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, United Kingdom.
  30. Lucy C Scott: Beatson West Of Scotland Cancer Centre, Glasgow, Scotland, United Kingdom.
  31. Cheryl A Palmer: Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, United Kingdom.
  32. Margaret Moody: Macmillan Unit, West Suffolk Hospital NHS Foundation Trust, Bury St Edmunds, United Kingdom.
  33. Mark J Churn: Worcestershire Acute Hospitals NHS Trust, Worcester, United Kingdom.
  34. Domenic Pilger: AstraZeneca, Cambridge, United Kingdom. ORCID
  35. Guido Zagnoli-Vieira: AstraZeneca, Cambridge, United Kingdom.
  36. Paul W G Wijnhoven: AstraZeneca, Cambridge, United Kingdom.
  37. Mukesh B Mukesh: Colchester General Hospital, East Suffolk & North Essex NHS Trust, Colchester, United Kingdom.
  38. Rebecca R Roylance: University College London Hospitals NHS Foundation Trust, London, United Kingdom. ORCID
  39. Philip C Schouten: Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  40. Nicola C Levitt: Oxford University Hospital NHS Foundation Trust, Oxford, United Kingdom.
  41. Karen McAdam: Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, United Kingdom.
  42. Anne C Armstrong: The Christie NHS Foundation Trust, Manchester, United Kingdom. ORCID
  43. Ellen R Copson: Cancer Sciences Academic Unit, University of Southampton, Southampton, United Kingdom.
  44. Emma McMurtry: EMC2 Clinical Consultancy Ltd, Sale, United Kingdom.
  45. Susan Galbraith: AstraZeneca, Cambridge, United Kingdom.
  46. Marc Tischkowitz: Department of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK. ORCID
  47. Elena Provenzano: Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
  48. Mark J O'Connor: AstraZeneca, Cambridge, United Kingdom. ORCID
  49. Helena M Earl: Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
PMID: 40360463 DOI: 10.1038/s41467-025-59151-0

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.

Associated Data

ClinicalTrials.gov | NCT03150576

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Grants

  1. CRUKE/14/048/Cancer Research UK (CRUK)
  2. 1994-A093777/AstraZeneca

MeSH Term

Humans
Female
Breast Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Piperazines
Phthalazines
Middle Aged
BRCA2 Protein
Neoadjuvant Therapy
Adult
BRCA1 Protein
Paclitaxel
Carboplatin
Antineoplastic Combined Chemotherapy Protocols
Aged

Chemicals

Poly(ADP-ribose) Polymerase Inhibitors
olaparib
Piperazines
Phthalazines
BRCA2 Protein
BRCA1 Protein
Paclitaxel
Carboplatin
BRCA2 protein, human
BRCA1 protein, human
Journal Article Randomized Controlled Trial Clinical Trial, Phase II Clinical Trial, Phase III

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